Diverse Lung Diseases Research Articles

Assessment of respiratory health status of workers in flour mills of Assiut

BackgroundWorking environment should not present a risk of injury or disease but many thousands of workers worldwide remain exposed to hazardous substances particularly in developing countries. Flour dust is one of those hazardous substances to which the flour mills workers are exposed to, inhalation of flour dust may cause diverse lung diseases with different severity of symptoms ranging from simple irritation to allergic reaction and chronic respiratory disorders, including asthma. Therefore, the present study was done to detect the prevalence of respiratory problems among flour mills workers.MethodsThe study was carried out in the flour mills of Assiut, it was a cross-sectional study among 203 workers. The study instruments were a semi-structured questionnaire about respiratory symptoms, chest examination and pulmonary function tests (PFT).ResultsThe age of the study workers ranged from 19 to 60 years old, 94.1% were males, 50.7% were from urban regions. Pulmonary function abnormalities were found in 36.4% of them and 20.7% were diagnosed with bronchial asthma. Significant relationships were detected between abnormal pulmonary function tests and workers ≥ 40 years old, low educational level and those who worked in the flour mills for ≥ 10 years.ConclusionsFlour dust cause respiratory symptoms and impair the pulmonary function of the flour mills workers and they may develop bronchial asthma which affect their work efficiency.RecommendationsMedical care must be provided regularly to the flour mills workers and safety measures are mandatory.Trial registrationClinicalTrials.gov. NCT03678519. Registered August 10, 2022.

Pulmonary Functions and Respiratory Symptoms of Wheat Flour Mill Workers in The Duhok District

Exposure to flour dust in flour mill factories may cause diverse lung diseases with different severity of symptoms ranging from simple irritation to allergic rhinitis or occupational asthma; long-term exposure to flour dust can cause chronic lung problems. The aim of this study is to examine the effect of exposure to flour dust on the respiratory system and pulmonary function of wheat flour mill workers in the Duhok district. A cross-sectional study was performed among 63 workers who had direct contact with wheat flour mills. The data were collected using a well-structured questionnaire, anthropometric measurements, and digital spirometry. The workers’ mean age ± (SD) was 29.79 ± 10.60 years. The current study showed the predicted Forced vital capacity (FVC) mean ± (SD) 105.34 L (±) 25.96 L, and the predicted Forced expiratory volume in one second (FEV1) mean ± (SD) 97.90 L (±) 18.65 L, and the predicted FEV1/FVC mean ± (SD) 95.82 L (±) 17.61 L. About 43(68.3%) of workers were normal,10(15.9%) had mild pulmonary obstruction followed by moderate restriction, 5(7.9%), and 3(4.8%) had mild pulmonary restriction. The mild obstructive disorder is more among normal Body Mass Index (BMI) persons, while restrictive disorders are more among overweight workers. This study showed no significant statistical association between PFTs and respiratory symptoms (sneezing, rhinorrhea, change of voice, dyspnea and cough), BMI, and the duration of working in the wheat flour mills.

MircroRNA Let-7a-5p in Airway Smooth Muscle Cells is Most Responsive to High Stretch in Association With Cell Mechanics Modulation.

Objective: High stretch (strain >10%) can alter the biomechanical behaviors of airway smooth muscle cells which may play important roles in diverse lung diseases such as asthma and ventilator-induced lung injury. However, the underlying modulation mechanisms for high stretch-induced mechanobiological responses in ASMCs are not fully understood. Here, we hypothesize that ASMCs respond to high stretch with increased expression of specific microRNAs (miRNAs) that may in turn modulate the biomechanical behaviors of the cells. Thus, this study aimed to identify the miRNA in cultured ASMCs that is most responsive to high stretch, and subsequently investigate in these cells whether the miRNA expression level is associated with the modulation of cell biomechanics. Methods: MiRNAs related to inflammatory airway diseases were obtained via bioinformatics data mining, and then tested with cultured ASMCs for their expression variations in response to a cyclic high stretch (13% strain) simulating in vivo ventilator-imposed strain on airways. Subsequently, we transfected cultured ASMCs with mimics and inhibitors of the miRNA that is most responsive to the high stretch, followed by evaluation of the cells in terms of morphology, stiffness, traction force, and mRNA expression of cytoskeleton/focal adhesion-related molecules. Results: 29 miRNAs were identified to be related to inflammatory airway diseases, among which let-7a-5p was the most responsive to high stretch. Transfection of cultured human ASMCs with let-7a-5p mimics or inhibitors led to an increase or decrease in aspect ratio, stiffness, traction force, migration, stress fiber distribution, mRNA expression of α-smooth muscle actin (SMA), myosin light chain kinase, some subfamily members of integrin and talin. Direct binding between let-7a-5p and ItgαV was also verified in classical model cell line by using dual-luciferase assays. Conclusion: We demonstrated that high stretch indeed enhanced the expression of let-7a-5p in ASMCs, which in turn led to changes in the cells’ morphology and biomechanical behaviors together with modulation of molecules associated with cytoskeletal structure and focal adhesion. These findings suggest that let-7a-5p regulation is an alternative mechanism for high stretch-induced effect on mechanobiology of ASMCs, which may contribute to understanding the pathogenesis of high stretch-related lung diseases.

Dimethyl fumarate prevents acute lung injury related cognitive impairment potentially via reducing inflammation

ObjectiveDimethyl fumarate (DMF) has been reported to exert a protective role against diverse lung diseases and cognitive impairment-related diseases. Thus this study aimed to investigate its role on acute lung injury (ALI) and related cognitive impairment in animal model.MethodsC57BL/6 mice were divided into four groups: control group, DMF group, ALI group, and ALI + DMF group. For ALI group, the ALI mice model was created by airway injection of LPS (50 μL, 1 μg/μL); for ALI + DMF group, DMF (dissolved in 0.08% methylcellulose) was treated twice a day for 2 days, and on the third day, mice were injected with LPS for ALI modeling. Mice pre-administered with methylcellulose or DMF without LPS injection (PBS instead) were used as the control group and DMF group, respectively. Morris water maze test was performed before any treatment (0 h) and 6 h after LPS-induction (54 h) to evaluate the cognitive impairment of mice. Next, the brain edema and blood brain barrier (BBB) permeability of ALI mice were assessed by brain water content, Evans blue extravasation and FITC-Dextran uptake assays. In addition, the effect of DMF on the numbers of total cells and neutrophils, protein content in BALF were quantified; the inflammatory factors in BALF, serum, and brain tissues were examined by ELISA, qRT-PCR, and Western blot assays. The effect of DMF on the cognitive impairment-related factor HIF-1α level in lung and brain tissues was also examined by Western blot.ResultsDMF reduced the numbers of total cells, neutrophils and protein content in BALF of ALI mice, inhibited the levels of IL-6, TNF-α and IL-1β in BALF, serum and brain tissues of ALI mice. The protein expressions of p-NF-κB/NF-κB and p-IKBα/IKBα was also suppressed by DMF in ALI mice. Morris water maze test showed that DMF alleviated the cognitive impairment in ALI mice by reducing the escape latency and path length. Moreover, DMF lessened the BBB permeability by decreasing cerebral water content, Evans blue extravasation and FITC-Dextran uptake in ALI mice. The HIF-1α levels in lung and brain tissues of ALI mice were also lessened by DMF.ConclusionIn conclusion, DME had the ability to alleviate the lung injury and cerebral cognitive impairment in ALI model mice. This protective effect partly associated with the suppression of inflammation by DMF.

Identification of novel cytokine biomarkers of hexanal exposure associated with pulmonary toxicity

We aimed to investigate whether exposure to low-molecular-weight saturated aliphatic aldehydes induces an airway inflammation related to lung toxicity. In previous studies, we identified that several aldehydes induced inflammatory responses through the secretion of pro-inflammatory cytokines.Here, we elucidate on whether hexanal exposure induces the lung inflammatory response through the secretion of cytokines. Hexanal is one of the aldehydes, which are major components of indoor environmental irritants. Based on a multiplexed cytokine antibody array, we investigated the cytokine expression profiles to identify the significant biomarkers of hexanal exposure and to predict the possibility of adverse effects on pulmonary toxicity using in vitro and in vivo model systems. We identified the cytokines as biomarkers involved in LEPTIN, Interleukin(IL)-10, MCP-1, and VEGF that showed similar expression patterns in both in vitro and in vivo models under hexanal exposure. These cytokines are known to be associated with diverse lung diseases, such as lung fibrosis, chronic obstructive pulmonary disease (COPD), and non-small cell lung cancer.Although further studies are needed to identify the mechanisms that underlie hexanal pulmonary toxicity, these results provide the key cytokine biomarkers in response to hexanal exposure and indicate meaningful mechanistic previewing that can be indirectly attributed to lung disease.

The pediatric microbiome and the lung.

Many pediatric lung diseases are characterized by infection. These infections are generally diagnosed, studied, and treated using standard culture methods to identify 'traditional pathogens'. Based on these techniques, healthy lungs have generally been thought to be sterile. However, recent advances in culture-independent microbiological techniques challenged this paradigm by identifying diverse microbes in respiratory specimens (respiratory microbiomes) from both healthy people and those with diverse lung diseases. In addition, growing evidence suggests a link between gastrointestinal microbiomes and inflammatory diseases of various mucosal surfaces, including airways. This article reviews the rapidly developing field of respiratory microbiome research, emphasizing recent progress made employing increasingly sophisticated technologies. Although many of the relevant studies have focused on adults with cystic fibrosis, recent research has included children and adults with other respiratory diseases, as well as healthy individuals. These studies suggest that even healthy children have airway microbiomes, and that both respiratory and gastrointestinal microbiomes often differ between healthy people and those with different types and severities of airway disease. The causal relationships between microbiomes, disease type and progression, and treatments such as antibiotics must now be defined. The advent of culture-independent microbiological techniques has transformed how we think about the relationship between microbes and airway disease. More research is required to translate these findings to improved therapies and preventive strategies.

Association of Wnt-Inducible Signaling Pathway Protein 1 Genetic Polymorphisms With Lung Cancer Susceptibility and Platinum-Based Chemotherapy Response

BackgroundPlatinum-based chemotherapy is the main treatment method for lung cancer patients. The genetic polymorphisms of Wnt-inducible signaling pathway protein 1 (WISP1) were reported to be associated with the development of diverse lung diseases. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response in Chinese lung cancer patients. Materials and MethodsA total of 556 lung cancer patients and 254 healthy controls were enrolled onto this study. The 28 polymorphisms of the WISP1 gene were genotyped by the Sequenom MassARRAY system. ResultsWe found that WISP1 rs16893344, rs2977530, rs2977537, and rs62514004 (P = .009, .033, .049, and .036, respectively) polymorphisms were related to susceptibility of lung cancer; and WISP1 rs11778573 (P = .023, nonsmokers), rs16893344 (P = .013, ≥ 50 years old), rs2977536 (P = .039, ≥ 50 years old; P = .044, nonsmokers; P = .047, non–small-cell lung cancer, respectively), rs2977549 (P = .013, smokers), and rs62514004 (P = .033, ≥ 50 years old) polymorphisms were significantly associated with platinum-based chemotherapy response in lung cancer patients. ConclusionGenotypes of WISP1 may be novel and useful biomarkers for diagnosis of lung cancer and evaluation of platinum-based chemotherapy response in lung cancer patients.

Pin1 Protein Regulates Smad Protein Signaling and Pulmonary Fibrosis

Interstitial pulmonary fibrosis is caused by the excess production of extracellular matrix (ECM) by Fb in response to TGF-β1. Here, we show that the peptidyl-prolyl isomerase Pin1 modulates the production of many pro- and antifibrogenic cytokines and ECM. After acute, bleomycin injury, Pin1(-/-) mice showed reduced, pulmonary expression of collagens, tissue inhibitors of metalloproteinases, and fibrogenic cytokines but increased matrix metalloproteinases, compared with WT mice, despite similar levels of inflammation. In primary fibroblasts, Pin1 was required for TGF-β-induced phosphorylation, nuclear translocation, and transcriptional activity of Smad3. In Pin1(-/-) cells, inhibitory Smad6 was found in the cytoplasm rather than nucleus. Smad6 knockdown in Pin1(-/-) fibroblasts restored TGF-β-induced Smad3 activation, translocation, and target gene expression. Therefore, Pin1 is essential for normal Smad6 function and ECM production in response to injury or TGF-β and thus may be an attractive therapeutic target to prevent excess scarring in diverse lung diseases.

Meningoteliomatosis pulmonar difusa: causa infrecuente de patrón micronodular

Pulmonary meningotheliomas are rare tumors that manifest as small nodules. They are most common in the sixth and seventh decades of life and are more common in women. Their cause is unknown and the imaging differential diagnosis should include other diseases that course with nodular patterns. Several authors have documented a statistically significant association between pulmonary meningotheliomatosis and diverse lung diseases, with adenocarcinoma of the lung being the most frequently associated disease. Very few cases of radiologically documented meningotheliomatosis have been reported. We present a case of a patient with a history of metachronous breast and rectal cancer. A micronodular pattern was observed in both lungs during CT examination to determine the extent of rectal cancer. The radiologic findings were initially interpreted as metastases and the definitive diagnosis of meningotheliomatosis was reached after lung biopsy.

An investigation on electronic nose diagnosis of lung cancer

The use of gas sensor arrays as medical diagnosis instruments has been proposed several years ago. Since then, the idea has been proven for a limited number of diseases. The case of lung cancer is particularly interesting because it is supported by studies that have shown the correlation between the composition of breath and the disease. However, it is known that many other diseases can alter the breath composition, so for lung cancer diagnosis it is necessary not only to detect generic alterations but those specifically consequent to cancer. In this paper an experiment, performed in the bronchoscopy unit of a large hospital, aimed at discriminating between lung cancer, diverse lung diseases and reference controls is illustrated. Results show not only a satisfactory identification rate of lung cancer subjects but also a non-negligible sensitivity to breath modification induced by other affections. Furthermore, the effects of some compounds frequently found in the breath of lung cancer subjects have also been studied. Results indicate that breath samples of control individuals drift towards the lung cancer group when added with either single or mixtures of these alleged cancer-related compounds.

Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury.

The primary function of neutrophils in host defense is to contain and eradicate invading microbial pathogens. This is achieved through a series of swift and highly coordinated responses culminating in ingestion (phagocytosis) and killing of invading microbes. While these tasks are usually performed without injury to host tissues, in pathologic circumstances such as sepsis, potent antimicrobial compounds can be released extracellularly, inducing a spectrum of responses in host cells ranging from activation to injury and death. In the lung, such inflammatory damage is believed to contribute to the pathogenesis of diverse lung diseases, including acute lung injury and the acute respiratory distress syndrome, chronic obstructive lung disease, and cystic fibrosis. In these disorders, epithelial cells are targets of leukocyte-derived antimicrobial products, including proteinases and oxidants. Herein, we review the mechanisms involved in the physiologic process of neutrophil transepithelial migration, including the role of specific adhesion molecules on the leukocyte and epithelial cells. We examine the responses of the epithelial cells to the itinerant leukocytes and their cytotoxic products and the consequences of this for lung injury and repair. This paradigm has important clinical implications because of the potential for selective blockade of these pathways to prevent or attenuate lung injury.

Regulation of Plasminogen Activator Inhibitor-1 Expression by Tumor Suppressor Protein p53

H1299 lung carcinoma cells lacking p53 (p53-/-) express minimal amounts of plasminogen activator inhibitor-1 (PAI-1) protein as well as mRNA. p53(-/-) cells express highly unstable PAI-1 mRNA. Transfection of p53 in p53(-/-) cells enhanced PAI-1 expression and stabilized PAI-1 mRNA. On the contrary, inhibition of p53 expression by RNA silencing in non-malignant human lung epithelial (Beas2B) cells decreased basal as well as urokinase-type plasminogen activator-induced PAI-1 expression because of accelerated degradation of PAI-1 mRNA. Purified p53 protein specifically binds to the PAI-1 mRNA 3'-un-translated region (UTR), and endogenous PAI-1 mRNA forms an immune complex with p53. Treatment of purified p53 protein with anti-p53 antibody abolished p53 binding to the 3'-UTR of PAI-1 mRNA. The p53 binding region maps to a 70-nucleotide PAI-1 mRNA 3'-UTR sequence, and insertion of the p53-binding sequence into beta-globin mRNA destabilized the chimeric transcript. Deletion experiments indicate that the carboxyl-terminal region (amino acid residues 296-393) of p53 protein interacts with PAI-1 mRNA. These observations demonstrate a novel role for p53 as an mRNA-binding protein that regulates increased PAI-1 expression and stabilization of PAI-1 mRNA in human lung epithelial and carcinoma cells.

PPARs in Lung Biology and Disease

In this special issue of PPAR Research, we have assembled a comprehensive and complementary group of review articles and original investigations that illustrate the pivotal role of the PPAR family of nuclear hormone receptors in the regulation of fundamental cellular events in the lung. The lung performs the vital function of gas exchange required for the delivery of oxygen to tissues. In performing this function, the lung is continuously exposed to a diverse array of microbial pathogens, allergens, and toxic particulate matter. These insults require immune and reparative responses that are appropriate, yet tightly regulated in order to maintain the delicate alveolar structures required for efficient gas exchange. PPARs and their obligatory heterodimer partners retinoid X receptors (RXR) are well known to regulate the expression of genes involved in lipid and glucose metabolism. More recently, these transcription factors have been shown to modulate developmental, inflammatory, and reparative responses, including those that occur in the lung. Articles included in this special issue highlight the importance of PPARs and RXR in lung biology and in the pathogenesis of lung disease.Both PPAR-γ and RXR participate in lung morphogenesis, including the processes of postnatal alveolar elastogenesis and maturation.The majority of studies reported to date support a role for PPAR-α and/or PPAR-γ in inhibiting the release of inflammatory mediators from lung immune and stromal/parenchymal cells in vitro, and dampening inflammation and damage in animal models of acute lung injury (ALI), ischemia-reperfusion injury, and allergic airways inflammation. Emerging evidence indicates that PPAR family members can also suppress proliferative and differentiation responses of lung epithelial cells, smooth muscle cells, and fibroblasts, which is of particular relevance to tissue remodeling and fibroproliferation that occur in chronic airways disease, ALI, pulmonary vascular disease, and pulmonary fibrosis. In contrast to these notable inhibitory effects, PPAR-γ can also activate key macrophage antimicrobial and reparative responses, in part by enhancing the expression of cell surface receptors required for ingestion of microbes and cellular debris present within the airspace. Finally, data is summarized to illuminate the central role of PPAR-γ in regulating critical aspects of lung tumor initiation, progression, and metastasis. Specific effects include promotion of tumor cell differentiation, induction of cell cycle arrest and apoptosis, suppression of angiogenesis, and modulation of immune/stromal cells within the tumor microenvironment. The field of PPAR research continues to be hindered by the nonselective effects of synthetic and naturally occurring agonists, the limited availability of potent and specific inhibitors, and the absence of ideal genetic models of PPAR deficiency. The introduction of new molecular tools and the generation of conditionally targeted and site specific (including lung epithelial cell-specific) PPAR-γ deficient mice will allow better distinction between PPAR-dependent and PPAR-independent effects. Moreover, the search for relevant endogenous PPAR ligands continues. The recently described nitroalkene species are appealing candidates, although the presence of these molecules in lung tissues has not yet been characterized. We thank the editors for the opportunity to share with the readership this important area of investigation. It is our hope that this special issue will serve as a catalyst for new initiatives in this exciting and rapidly evolving field. Observations made at the bench have already transitioned to the bedside, as trials assessing effects of PPAR-γ agonists in the treatment of diverse lung diseases, including asthma and lung cancer, are ongoing. Theodore J. Standiford Jesse Roman

Elevated Inorganic Phosphate Stimulates Akt-ERK1/2-Mnk1 Signaling in Human Lung Cells

Inorganic phosphate (Pi) plays a critical role in diverse cellular functions. Among three classes of sodium/phosphate co-transporters (NPTs), two types have been identified in mammalian lung. The potential importance of Pi as a novel signaling molecule and pulmonary expression of NPTs with poor prognosis of diverse lung diseases including cancer have prompted us to begin to define the pathways by which Pi regulates nontumorigenic human bronchial epithelial cells. Pi activates Akt phosphorylation on Thr308 specifically, and activated signal transmits on the Raf/MEK/ERK signaling. Here, we report that Pi controls cell growth by activating ERK cascades and by facilitating the translocation of Mnk1 from cytosol into nucleus through an Akt-mediated MEK pathway. Sequentially, translocated Mnk1 increases eIF4E-BP1 phosphorylation. As a result, Pi stimulates cap-dependent protein translation. Such Akt-mediated signaling of inorganic phosphate may provide critical clues for treatment as well as prevention of diverse lung diseases.

디젤분진이 폐포대식세포에서 nitric oxide의 생성과 inducible nitric oxide synthase의 발현 및 nitrotyrosilated-protein의 형성에 미치는 효과

Epidemiological studies have demonstrated an association between exposure to diesel exhaust particles (DEP) and adverse cardiopulmonary effects. Despite the epidemiological proof, the pathogenesis of DEP-related pulmonary diseases remain poorly understood. So, comprehensive in vivo and in vitro researches are required to know the effects of DEP on diverse lung diseases. Alveolar macrophages (AM) and airway epithelial cells are known as important cellular targets in DEP-induced lung diseases. Other studies have shown that nitric oxide (NO) is involved in particle matter induced lung injury. The present study was undertaken to determine whether DEP has an synergistic effects on lipopolysaccharide (LPS)-induced NO formation and inducible nitric oxide synthase (iNOS) with nitrotyrosilated-protein formation in cultured primary alveolar macrophages. The formation of NO was determined through the Griess reaction in the cultured medium and iNOS with nitrotyrosilated-proteins are analyzed by immunohistochemical staining and Western analysis. The results indicate that DEP exposure does not induce NO formation by itself, however DEP showed significant synergistic effects on LPS-induced NO formation. So, our results suggest that DEP inhalation could aggravate inflammatory lung disease through NO formation